Ustekinumab

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Continuing Education Activity

Ustekinumab is a medication used to manage and treat a variety of inflammatory conditions, including psoriasis, psoriatic arthritis, and inflammatory bowel disease. It is in the monoclonal antibody class of medications. This activity reviews the indications, action, and contraindications for ustekinumab as a valuable agent in treating inflammatory diseases. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of psoriasis, psoriatic arthritis, and inflammatory bowel disease.

Objectives:

  • Explain the mechanism of action of ustekinumab.
  • Describe the indications for the use of ustekinumab.
  • Review the potential adverse event that can accompany ustekinumab use.
  • Outline strategies utilized by healthcare teams to improve care coordination and communication when ustekinumab is being administered.

Indications

Ustekinumab is a human monoclonal antibody typically used to treat moderate to severe plaque psoriasis, psoriatic arthritis, moderate to severe Crohn disease, or moderate to severe ulcerative colitis (inflammatory bowel disease). Ustekinumab mediates the body's T-cell response by acting as an antagonist against interleukin-12 (IL12) and interleukin-23 (IL23). The drug is FDA approved for use in moderate to severe plaque psoriasis (Ps), particularly in those patients who are candidates for phototherapy or systemic therapy, aged 6 or older. Patients with active psoriatic arthritis (PsA) may use ustekinumab as monotherapy or in combination with methotrexate.

More recently, ustekinumab has been approved for moderate to severely active Crohn disease (CD) and ulcerative colitis (UC). While ustekinumab has not received FDA approval for many other inflammatory mediated diseases, it has been used off label for the treatment of hidradenitis suppurativa, Takayasu arteritis, giant cell arteritis, Behcet disease, myelodysplastic syndrome, pyoderma grangrenosum, pityriasis rubra pilaris, synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, Lichen planus, atopic dermatitis as well as systemic lupus erythematosus.[1][2][3][4][5][6][7][8][9][10][11][12]

Mechanism of Action

IL-12 and IL-23 are cytokines that modulate lymphocyte function and have been implicated in the pathogenesis of inflammatory diseases such as psoriasis, psoriatic arthritis, multiple sclerosis, and inflammatory bowel disease.[13] IL-12 is a cytokine produced by antigen-presenting cells such as dendritic cells and macrophages involved in the development of Th1 cells, which secrete interferon-gamma.[14] 

IL-23 is a pro-inflammatory cytokine predominantly produced by dendritic cells, monocytes, and macrophages, which causes the differentiation and activation of Th17. Both cytokines share a p40 subunit.[15] As a human monoclonal IgG1 antibody, ustekinumab blocks the p40 subunit, and this antagonistic action inhibits the interaction of these cytokines with the IL-12Rβ1 receptor. The IL-12Rβ1 receptor is found on the surface of NK cells and T cells. In doing so, ustekinumab can inhibit IL-12 and IL-23 signaling, activation, and cytokine production resulting in downregulation of the immune system, which reduces inflammation and alters the body's immune response.[16] Serum concentrations are proportional to dose.[17]

Administration

Ustekinumab is available for injection in pre-filled syringes and vials. The drug is administered by either subcutaneous injection or intravenous infusion. The dosage and administration recommendations depend on the particular indication for treatment and the patient's weight. 

Dosage Forms and Strengths

Subcutaneous injection:

  • Injection: 45 mg/0.5 mL or 90mg/mL solution in a pre-filled syringe
  • Injection: 45 mg/0.5 mL solution in a single-dose vial

Intravenous infusion:

  • Injection: 130 mg/26 mL (5 mg/mL) in a single-dose vial

Dosage and Administration

Psoriasis adult S/C recommended dosage:

  • Less than or equal to 100 kg: 45 mg administered subcutaneously initially, followed by another injection four weeks later and then every 12 weeks
  • Greater than 100 kg: 90 mg administered subcutaneously initially, followed by another injection four weeks later and then every 12 weeks.[18]

Psoriatic arthritis adult S/C recommended dosage:

  • Less than or equal to 100 kg: 45 mg administered subcutaneously initially, followed by another injection four weeks later and then every 12 weeks
  • Greater than 100 kg with co-existent moderate-severe plaque psoriasis: 90mg administered subcutaneously initially, followed by another injection four weeks later and then every 12 weeks.[19][20]

Psoriasis pediatric patients recommended subcutaneous dosage:

Doses are administered initially, four weeks later, and then every 12 weeks.[21]

  • Weight < 60 kg: 0.75 mg/kg subcutaneously
  • Weight 60 to 100 kg: 45 mg subcutaneously
  • Weight > 100 kg: 90 mg subcutaneously

Crohn disease and ulcerative colitis treatment are based on an initial intravenous weight-based infusion followed by a subcutaneous maintenance schedule.[22][23]

Initial infusion dosage:

  • Weight < 55 kg: 260 mg (2 vials)
  • Weight 55 to 85 kg : 390 mg (3 vials)
  • Weight > 85 kg: 520 mg (4 vials)

Crohn disease and ulcerative colitis recommended adult S/C maintenance dosage:

  • 90 mg subcutaneously eight weeks after initial intravenous administration and every eight weeks after that.

Renal dosing (including both hemodialysis and peritoneal dialysis) and hepatic dosing are undefined.

Adverse Effects

Mild side effects (as outlined below) have been reported among ustekinumab users. Major side effects such as serious infections and major adverse cardiovascular events are rare. The adverse event profile is similar between psoriasis and psoriatic arthritis patients. However, abdominal pain, fever, and diarrhea have been reported for maintenance doses of ustekinumab for Chrohn and ulcerative colitis patients.[24][25][26][27]

The following adverse effects have been reported:

Serious Reactions

  • Severe infections or exacerbation/reactivation of existing infection (bacterial, mycobacterial, fungal, viral)
  • Malignancy (e.g., non-melanoma skin cancer)
  • Hypersensitivity reactions/anaphylaxis
  • Reversible posterior leukoencephalopathy syndrome
  • Cryptogenic organizing pneumonia
  • Interstitial or eosinophilic pneumonia

Common Reactions

  • Nasopharyngitis
  • Headache
  • Fatigue
  • Vomiting after induction in inflammatory bowel disease
  • Injection site erythema
  • Bronchitis/upper respiratory tract infection
  • Sinusitis
  • Abdominal pain, fever, influenza, and diarrhea while used for maintenance therapy in inflammatory bowel disease
  • Back pain

Other Reported Reactions

  • Pruritus
  • Pustular and erythrodermic psoriasis
  • Exfoliative dermatitis 

Ustekinumab has been generally well tolerated by patients in clinical trials, with most adverse events being mild in severity.[28]

Contraindications

Absolute Contraindications

  • Hypersensitivity to ustekinumab or any of the excipients 
  • Active infection 
  • Active tuberculosis

Caution Recommended

  • Latex hypersensitivity (with the pre-filled syringe dose form)
  • Patients aged over 60
  • Chronic or recurrent infections
  • Latent tuberculosis or those with TB risk
  • Malignancy of a history of malignancy
  • prolonged immunosuppressant therapy
  • Allergen immunotherapy
  • Photochemotherapy (PUVA)

As with all biological medications, appropriate screening for severe infection must be carried out before beginning a drug such as ustekinumab; this includes screening for infections such as tuberculosis, HIV, hepatitis B, and hepatitis C and treatment if identified. Providers must exercise caution in recommending treatment for elderly patients, patients with a history of malignancy, or a predisposition to infection.[29]

Ustekinumab can be used during pregnancy. Based on limited human data, there is no expected risk of fetal harm, and teratogenicity has not been demonstrated in animal studies at up to 100 times the maximum recommended human dose (MRHD). The drug may also be used during breastfeeding; no human data is currently available, but there is no expectation of infant harm based on the drug's properties. No human data exist regarding ustekinumab's effect on milk production.[30][31]

Monitoring

Baseline Monitoring

  • Routine blood tests: complete blood count, urea and electrolytes, liver function tests, and inflammatory markers (CRP/ESR)
  • Varicella antibody status should be clarified, and vaccination considered in appropriate patients
  • Screening for tuberculosis should be done with a chest X-ray and interferon-gamma release assay[29]
  • Hepatitis B, C, and HIV
  • Pregnancy testing should be performed in female patients where pregnancy is a possibility

Ongoing Monitoring[32][33]

  • The patients must be monitored clinically for the development of severe infections, including TB, jaundice, malignancy, non-infectious pneumonia, posterior reversible encephalopathy syndrome, or serious skin conditions such as exfoliative dermatitis or erythrodermic psoriasis. Patients additionally should be encouraged to report any concerning symptoms. 
  • Routine blood tests, including full blood count, urea, electrolytes, liver function tests, and inflammatory markers (CRP/ESR), should be checked approximately every 4 to 6 months.[32][33] 
  • Clinical monitoring for efficacy should be carried out using disease-specific measuring systems for psoriasis, psoriatic arthritis, and inflammatory bowel disease. 
  • Re-testing for hepatitis and HIV can be considered if clinically indicated.
  • There are experimental data to suggest that monitoring serum drug levels may be beneficial during ustekinumab treatment, but this is not the current standard of care.[34]

Toxicity

Ustekinumab is a well-tolerated drug with a favorable safety profile. No dose-related or cumulative toxicity was observed during follow-up studies.[35] Given that ustekinumab is a biologic medication that inhibits the normal functioning of the immune system, there is theoretically an increased risk of infection, and clinical evidence of infection should be evaluated at each follow-up visit. Limited pregnancy and breastfeeding data are available, and more studies are needed to confirm safe use during pregnancy.[36] 

There have been reports of the rapid development of cutaneous squamous cell carcinoma in those patients treated with ustekinumab. These patients often had risk factors for developing this type of cancer, such as being older (greater than 60) and having undergone phototherapy or other immunosuppressant treatment. Patients should be monitored closely for the development of non-melanoma skin cancers.[37] As with all biological drugs, live vaccines should not be administered while on ustekinumab treatment.[38]

Enhancing Healthcare Team Outcomes

The management of inflammatory diseases such as psoriasis, psoriatic arthritis, and inflammatory bowel disease is complex and associated with a high-cost burden. The rational and cost-effective use of biological medications, such as ustekinumab, is a key component in managing these diseases. To achieve the desired outcome, an interprofessional healthcare team approach is necessary. Internal medicine clinicians (including mid-level practitioners such as nurse practitioners and physician assistants) may work with specialists, including rheumatologists, gastroenterologists, or dermatologists, to confirm the diagnosis and decide on a treatment course. Nurses facilitate the preparation and administration of medications, as well as monitoring patients after use; they should immediately report any concerns to the ordering/prescribing clinician. Pharmacists can ensure no relevant drug-drug interactions exist, evaluate the relevance of contraindications to treatment, verify dosing is correct (especially inasmuch as ustekinumab utilizes weight-based dosing regimens), and ensure the appropriateness of prescriptions. All clinical personnel need to participate in patient counseling, educate the patient regarding potential adverse events, signs of therapeutic failure, and provide access to resources and points of contact should they need to reach out to the interprofessional team. Social workers identify barriers to compliance and provide resources to patients. Each member of the interprofessional team's contributions can provide expertise from their discipline to help drive a positive outcome for patients with potentially fewer adverse events and improve the effectiveness of the broader healthcare system. [Level 5]


Article Details

Article Author

Matthew Colquhoun

Article Editor:

Alysia K. Kemp

Updated:

4/3/2022 11:12:35 AM

PubMed Link:

Ustekinumab

References

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